chr12-111418301-T-A

Variant names:

• chr12-111418301-T-A
• rs775725883
• NM_005475.3:c.156T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005475.3(SH2B3):​c.156T>A​(p.His52Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,304 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H52P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 1 publications found

Genes affected

SH2B3 (HGNC:29605): (SH2B adaptor protein 3) This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

SH2B3 Gene-Disease associations (from GenCC):

• syndromic disease

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• acute lymphoblastic leukemia

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• growth retardation-mild developmental delay-chronic hepatitis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• primary familial polycythemia due to EPO receptor mutation

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• thrombocythemia 1

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.156T>A	p.His52Gln	missense	Exon 2 of 8	NP_005466.1	Q9UQQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.156T>A	p.His52Gln	missense	Exon 2 of 8	ENSP00000345492.2	Q9UQQ2
	SH2B3	ENST00000896496.1		c.156T>A	p.His52Gln	missense	Exon 2 of 8	ENSP00000566555.1
	SH2B3	ENST00000935782.1		c.156T>A	p.His52Gln	missense	Exon 2 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381304 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 682506

African (AFR) AF: 0.00 AC: 0 AN: 30600

American (AMR) AF: 0.00 AC: 0 AN: 35740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24936

East Asian (EAS) AF: 0.00 AC: 0 AN: 35252

South Asian (SAS) AF: 0.00 AC: 0 AN: 79544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4982

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078314

Other (OTH) AF: 0.00 AC: 0 AN: 57566

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.052
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.023	D
Sift4G	Benign	0.067	T
Polyphen		0.95	P
Vest4		0.26
MutPred		0.81		Gain of MoRF binding (P = 0.1095)
MVP		0.72
MPC		1.3
ClinPred		0.39	T
GERP RS		3.1
PromoterAI		0.11	Neutral
Varity_R		0.10
gMVP		0.34
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs775725883; hg19: chr12-111856105;